Huntington's disease (“HD”) is a neurodegenerative brain disorder with a juvenile or adult onset. It slowly destroys an affected individual's ability to walk, think, talk and reason. Symptoms include changes in cognitive ability, such as impaired short-term memory and a decreased ability to concentrate; changes in mood, such as the development of mood swings, depression and irritability; and changes in coordination and physical movement such as clumsiness, involuntary movements and twitching. These symptoms gradually worsen until HD patients die, approximately 15-20 years after the onset of the disease.
While the biochemical cause of HD is not yet fully understood, it is now known that HD is inherited as an autosomal dominant trait. This inheritance feature means that every individual who inherits a mutated (expanded) HD gene from either parent will develop the disease.
One breakthrough in research regarding HD has been the identification of the mutated gene that causes HD. Based on this breakthrough, researchers and physicians now can predict which individuals will develop HD. Specifically, researchers and physicians can predict which individuals will develop HD by counting the number of “CAG repeats” that exist within a given individual's HD gene. If a person has 35 or fewer CAG repeats in both of their HD genes, that person will not develop HD. If a person has more than 35 CAG repeats in either of their HD genes, that person will develop the disease. The more CAG repeats a person has over 35, the earlier the person will develop the symptoms of HD.
The HD gene encodes for a protein called “huntingtin” (also known as “htt”). The exact function of huntingtin is not known. The expression of a mutant, expanded huntingtin protein is known to be the cause of HD, however. Some of the evidence that has led scientists to this conclusion includes mouse studies showing that the introduction of an expanded HD transgene in the mouse leads to the pathological and behavioral features of HD and its removal can resolve these effects. Thus, suppressing the production of huntingtin in brain cells may prevent or alleviate the symptoms or occurrence of HD.
Recent developments in genetic technologies have made the selective suppression of certain proteins, such as huntingtin, possible. Some background in the art is required to understand the potential impact of these technologies. Generally, for a protein to exert an effect, the cell that will use the protein must create it. To create a protein the cell first makes a copy of the protein's gene sequence in the nucleus of the cell. This copy of the gene sequence that encodes for the protein (called messenger RNA (“mRNA”)) leaves the nucleus and is trafficked to a region of the cell containing ribosomes. Ribosomes read the sequence of the mRNA and create the protein for which it encodes. This process of new protein synthesis is known as translation. A variety of factors affect the rate and efficiency of protein translation. Among the most significant of these factors is the intrinsic stability of the mRNA itself. If the mRNA is degraded quickly within the cell (such as before it reaches a ribosome), it is unable to serve as a template for new protein translation, thus reducing the cell's ability to create the protein for which it encoded.
Based on the foregoing, the technology of RNA interference (“RNAi”) has emerged. RNA interference is, in fact, a naturally-occurring mechanism for suppressing gene expression and subsequent protein translation. RNA interference suppresses protein translation by either degrading the mRNA before it can be translated or by binding the mRNA and directly preventing its translation. This naturally-occurring mechanism of RNA interference can also be artificially induced to occur in cells. For example, RNA interference can be achieved by introducing into cells short, double-stranded nucleic acid oligonucleotides corresponding to the mRNA for the gene to be suppressed, or by introducing into cells a sequence of DNA that encodes for a short, hairpin transcript of nucleic acids that folds back upon itself and forms a short, double-stranded nucleic acid oligonucleotide following further processing in the cell. This technology provides a means to suppress the expression of huntingtin in cells. The suppression of huntingtin in cells can be useful in the study of HD pathogenesis. Suppressing huntingtin in a patient also could prevent or alleviate the symptoms of HD.